RGS10 Negatively Regulates Platelet Activation and Thrombogenesis

Abstract

Regulators of G protein signaling (RGS) proteins act as GTPase activating proteins to negatively regulate G protein-coupled receptor (GPCR) signaling. Although several RGS proteins including RGS2, RGS16, RGS10, and RGS18 are expressed in human and mouse platelets, the respective unique function(s) of each have not been fully delineated. RGS10 is a member of the D/R12 subfamily of RGS proteins and is expressed in microglia, macrophages, megakaryocytes, and platelets. We used a genetic approach to examine the role(s) of RGS10 in platelet activation in vitro and hemostasis and thrombosis in vivo. GPCR-induced aggregation, secretion, and integrin activation was much more pronounced in platelets from Rgs10-/- mice relative to wild type (WT). Accordingly, these mice had markedly reduced bleeding times and were more susceptible to vascular injury-associated thrombus formation than control mice. These findings suggest a unique, non-redundant role of RGS10 in modulating the hemostatic and thrombotic functions of platelets in mice. RGS10 thus represents a potential therapeutic target to control platelet activity and/or hypercoagulable states.

Platelets at the vascular interface

“…Consistently, it was previously shown that knockdown of RGS18[24,25], RGS10[26] or mutation of the RGS binding site on Gαi[27] results in increased platelet reactivity. At this ISTH conference, Gupta et al confirmed that knockdown of RGS10 results in a gain of platelet function, in particular in response to stimulation by the second wave mediators, ADP and TxA 2 [28].…”

“…Duration and intensity of the GPCR signal are limited not only by receptor desensitization but also by Regulator of G-protein Signaling (RGS) proteins that increase the rate of GTP hydrolysis and return G proteins to the inactive state. Consistently, it was previously shown that knockdown of RGS18,24,25 RGS10,26 or mutation of the RGS binding site on Gαi 27 results in increased platelet reactivity. At this ISTH conference, Gupta et al confirmed that knockdown of RGS10 results in a gain of platelet function, in particular in response to stimulation by the second wave mediators, ADP and TxA 2 .…”

RGS10 Regulates the Expression of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha through a G Protein–Independent Mechanism

“…RGS10 regulates cellular physiology and fundamental signaling pathways in microglia (Lee et al, 2008(Lee et al, , 2011, macrophages (Lee et al, 2013), T-lymphocytes (Lee et al, 2016), neurons (Lee et al, 2012), osteoclasts Yang et al, , 2013, cardiomyocytes (Miao et al, 2016), platelets (Hensch et al, 2016(Hensch et al, , 2017, and cancer cells (Hooks et al, 2010;Ali et al, 2013;Cacan et al, 2014;Hooks and Murph, 2015). However, despite its small size and seemingly simple function as a G protein GAP, the molecular mechanisms accounting for RGS10 effects have not been defined.…”

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

“…Washed platelets were prepared as described previously 38, 41, 42. Mouse blood was collected as discussed above and mixed with phosphate‐buffered saline, pH 7.4, and was incubated with PGI 2 (10 ng/mL; 5 minutes), followed by centrifugation at 237 g for 10 minutes at room temperature.…”